Pleiotropic functions of cytokines and STAT5

细胞因子和 STAT5 的多效性功能

• 批准号: 13470070
• 负责人: KITAMURA Toshio
• 金额: $ 7.55万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470070/
• 关键词: Cytokine; signal transduction; STAT5; IL-6; NFκB; macrophage; M1; NFKB; START5

We have been working on molecular mechanisms of the pleiotropic functions of cytokines using the constitutively active mutants of STAT5 (Onishi et al. Mol Cell Biol, 1998; Ariyoshi et al. J Biol Chem, 2000) which we identified by PCR-driven random mutagenesis followed by retrovirus-mediated expression screening. STAT5 is a transcription factor known to induce the expression of a variety of target genes. We previously demonstrated that STAT5 could induce proliferation, differentiation, and apoptosis in the same cells through induction of pim-1, p21 and SOCS1, respectively (Nosaka et al, EMBO J, 1999). We have now identified a novel mechanism by which the constitutively active STAT5 induced macrophage differentiation of M1 cells ; the active STAT5 induced macrophage differentiation via autocrine production of IL-6 (Kawashima et al. J Immunol, 2001). Interestingly, the promoter of the IL-6 gene does not contain the biding site of STAT5, and the induction of IL-6 by the active STAT5 was mediated through activation of NFkB. Now we are investigating the underlying molecular mechanism, and the preliminary results indicate that a secreted protein induced by STAT5 activation is responsible for IL-6 production (Nakamura et al. J Biol Chem, 2002). The identification of this secreted protein is now ongoing.

我们一直在使用STAT5的组成性活性突变体（Onishi等人Mol Cell Biol，1998; Ariyoshi etal。Jbiol Chem，2000）进行了细胞因子的多效功能的分子机制，我们通过PCR-drien驱动的随机突变发生，然后进行了逆转录病毒介导的表达筛查。 STAT5是已知诱导各种靶基因表达的转录因子。我们先前证明，STAT5分别通过诱导PIM-1，P21和SOCS1诱导同一细胞中的扩散，分化和凋亡（Nosaka等，Embo J，1999）。现在，我们已经确定了一种新型机制，该机制通过该机制诱导了M1细胞的巨噬细胞分化。活性STAT5通过IL-6的自分泌产生诱导巨噬细胞分化（Kawashima等人J Immunol，2001）。有趣的是，IL-6基因的启动子不包含STAT5的划船位点，而Active Stat5诱导IL-6是通过激活NFKB介导的。现在，我们正在研究基本的分子机制，初步结果表明，STAT5激活诱导的分泌蛋白质是IL-6产生的原因（Nakamura etal。JBiol Chem，2002年）。该分泌蛋白的鉴定现在正在进行中。

项目成果

Nosaka, T., Morita, S., Kitamura, H., Nakajima, H., Shibata, F., Morikawa, Y., Kataoka, Y., Ebihara, Y., Kawashima, T., Itoh, T., Ozaki, K., Senba, E., Tsuji, K., Makishima, F., Yoshida, N., and Kitamura, T.: "Mammalian Twisted Gastrulation Is Essential f

野坂，T.，森田，S.，北村，H.，中岛，H.，柴田，F.，森川，Y.，片冈，Y.，海老原，Y.，川岛，T.，伊藤，T.，

Perez, O.D.: "Acitivation of the PKB/AKT pathway by ICAM-2"Immunity. 16. 51-65 (2002)

Perez, O.D.：“ICAM-2 激活 PKB/AKT 通路”免疫。

Yujiri, T., Nawata, R., Takahashi, T., Sato, Y., Tanizawa, Y, Kitamura, T., and Oka, Y.: "MEK kinase 1 interacts with focal adhesion kinase and regulates insulin receptor substrate-1 expression"J. Biol. Chem.. 278. 3846-3851 (2003)

Yujiri, T.、Nawata, R.、Takahashi, T.、Sato, Y.、Tanizawa, Y、Kitamura, T. 和 Oka, Y.：“MEK 激酶 1 与粘着斑激酶相互作用并调节胰岛素受体底物 -

Komano, H.: "A new functional screening system for identification of DNA encoding a regulator of γ-cleavage"J. Biol. Chem.. 277. 39627-39633 (2002)

Komano, H.：“用于鉴定编码 γ-裂解调节剂的 DNA 的新功能筛选系统”J. Biol. 277. 39627-39633 (2002)

Gugasyan, R., Quilici, C., I, S.T., Grail, D., Verhagen, A.M., Roberts, A., Kitamura, T., Dunn, A.R., and Lock, P.: "Dok-related protein negatively regulates T cell development ts RasGTPase activating protein and Nck docking sites"J. Cell Biol.. 158. 115-

Gugasyan, R.、Quilici, C.、I、S.T.、Grail, D.、Verhagen, A.M.、Roberts, A.、Kitamura, T.、Dunn, A.R. 和 Lock, P.：“Dok 相关蛋白负调节